Based on clinical evidence suggesting age-relaled differences in the acquisition of bronchial hyperreactivity following an acute inflammatory insult to the airways, two interrelated hypotheses are raised: I: That the mechanisms regulating non-specific airway reactivity vary maturationally; II: That acute airways inflammation alters bronchial reactivity in an age-dependent manner. In addressing these hypotheses, airway responsiveness will be determined in rabbits of varying post-natal age: a) in vivo, based on pulmonary resistance and dynamic compliance responses to administered contractile agonists; and b) in vitro, based on the effects of these agonists in isolated, airway smooth muscle. A: To assess the maturation of mechanisms regulating airway responsiveness to histamine and methacholine, we will examine whether ontogenetic differences exist in: 1) the dissociation constants of histamine and cholinergic receptor agonists in maturing airways; 2) the opposing airway dilatory histamine H2 - receptor influence; 3) the histamine-induced reflex parasympathetic and local cholinergic influencas on airway function; 4) the effects of protein kinase C activation on airway contractility; and 5) the airway modulatory action of the Na+-K+ electrogenic pump. B: To assess the maturation of mechanisms regulating airway beta- adrenergic responsiveness, we will examine the ontogenetic changes in: 1) post-adrenoceptor-mediated activation of adenylate cyclase; and 2) the influence of the N, guanine nucleotide regulatory protein on the beta-adrenoceptor-adenylate cyclase system. C: To assess the maturation of temperature-induced changes in airway contractility, we will determine whether ontogenetic differences exist in the effects of airway cooling on: 1) the dissociation constants of histamine and cholinergic receptor agonists in maturing airways; 2) histamine H2-receptor-mediated activity; and 3) the airway neuronal Na+-K+ electrogenic pump. In separate studies, the are-related effects of acute airways; inflammation on bronchial reactivity will be evaluated following: a) intra- pulmonary instillation of the phlogistic agent C5a des Arg; b) ozone inhalation; and c) antigenspecific airway sensitization. The inflammation-associated changes in reactivity will be further examined maturationally with respect to alterations in the contributions of the above mechanisms (i.e., A-C) regulating airway function. Collectively, the proposed studies should provide significant new insights into the interrelationship between maturation, bronchial reactivity and inflammation.